Search

ObjectivesSlow expansion of multiple sclerosis (MS) lesions has been shown to significantly contribute to disease progression. However, accurate assessment of this metric remains challenging. We investigated whether the long-term damage caused by slow-burning inflammation at the rim of chronic MS lesions can be predicted within timeframe of a typical clinical trial, using surrogate imaging markers.MethodsPre- and post-gadolinium 3D-T1, 3D FLAIR and diffusion tensor images were acquired from 42 patients with MS. Lesion expansion was analysed annually between baseline and 48 months. The volume of chronic lesion expansion was stratified by the degree of tissue damage within the expanding component of the lesion, measured by a progressive volume/severity index (PVSI). Central brain atrophy (CBA) and the degree of tissue loss inside chronic lesions (measured by the change of T1 intensity and MD) were used as surrogate markers.ResultsCBA measured after 2 years of follow-up predicted PVSI at 4 years with a high degree of accuracy (r=0.90, pInterpretationCBA and, to a lesser degree, the change in MD within chronic MS lesions, measured over 2 years are reliable and sensitive predictors of the extent and severity of long-term lesion expansion.

Glaucoma is a complex neurodegenerative disease characterized by optic nerve damage and apoptotic retinal ganglion cell (RGC) death, and is the leading cause of irreversible blindness worldwide. Among the sphingosine 1-phosphate receptors (S1PRs) family, S1PR1 is a highly expressed subtype in the central nervous system and has gained rapid attention as an important mediator of pathophysiological processes in the brain and the retina. Our recent study showed that mice treated orally with siponimod drug exerted neuroprotection via modulation of neuronal S1PR1 in experimental glaucoma. This study identified the molecular signaling pathway modulated by S1PR1 activation with siponimod treatment in RGCs in glaucomatous injury. We investigated the critical neuroprotective signaling pathway in vivo using mice deleted for S1PR1 in RGCs. Our results showed marked upregulation of the apoptotic pathway was associated with decreased Akt and Erk1/2 activation levels in the retina in glaucoma conditions. Activation of S1PR1 with siponimod treatment significantly increased neuroprotective Akt and Erk1/2 activation and attenuated the apoptotic signaling via suppression of c-Jun/Bim cascade and by increasing Bad phosphorylation. Conversely, deletion of S1PR1 in RGCs significantly increased the apoptotic cells in the ganglion cell layer in glaucoma and diminished the neuroprotective effects of siponimod treatment on Akt/Erk1/2 activation, c-Jun/Bim cascade, and Bad phosphorylation. Our data demonstrated that activation of S1PR1 in RGCs induces crucial neuroprotective signaling that suppresses the proapoptotic c-Jun/Bim cascade and increases antiapoptotic Bad phosphorylation. Our findings suggest that S1PR1 is a potential therapeutic target for neuroprotection of RGCs in glaucoma.

Background: Expansion of chronic multiple sclerosis (MS) lesion is associated with slow-burning inflammation at lesion rim. However, the underlying mechanisms leading to expansion are not fully understood. Objective: To investigate the relationship between diffusivity markers of demyelination and axonal loss in perilesional white matter and lesion expansion in relapsing-remitting MS (RRMS). Methods: T1, FLAIR and diffusion tensor images were acquired from 30 patients. Novel single-streamline technique was used to estimate diffusivity in lesions, perilesional white matter and normal-appearing white matter (NAWM). Results: Significant association was found between baseline periplaque radial diffusivity (RD) and subsequent lesion expansion. Conversely, periplaque axial diffusivity (AD) did not correlate with lesion growth. Baseline RD (but not AD) in periplaque white matter of expanding lesions was significantly higher compared with non-expanding lesions. Correlation between increase of both RD and AD in the periplaque area during follow-up period and lesion expansion was noticeably stronger for RD. Increase of RD in periplaque area was also much higher compared to AD. There was significant increase of AD and RD in the periplaque area of expanding, but not in non-expanding, lesions. Conclusion: Periplaque demyelination is likely to be an initial step in a process of lesion expansion and, as such, potentially represents a suitable target for remyelinating therapies.

Background: Decreased motion perception has been suggested as a marker for visual pathway demyelination in optic neuritis (ON) and/or multiple sclerosis (MS). Objectives: To examine the influence of neuro-axonal damage on motion perception in MS and neuromyelitis optica spectrum disorders (NMOSD). Methods: We analysed motion perception with numbers-from-motion (NFM), visual acuity, (multifocal (mf)) VEP, optical coherence tomography in patients with MS ( n = 38, confirmatory cohort n = 43), NMOSD ( n = 13) and healthy controls ( n = 33). Results: NFM was lower compared with controls in MS ( B = −12.37, p < 0.001) and NMOSD ( B = −34.5, p < 0.001). NFM was lower in ON than in non-ON eyes ( B = −30.95, p = 0.041) in NMOSD, but not MS. In MS and NMOSD, lower NFM was associated with worse visual acuity ( B = −139.4, p < 0.001/ B = −77.2, p < 0.001) and low contrast letter acuity ( B = 0.99, p = 0.002/ B = 1.6, p < 0.001), thinner peripapillary retinal nerve fibre layer ( B = 1.0, p < 0.001/ B = 0.92, p = 0.016) and ganglion cell/inner plexiform layer ( B = 64.8, p < 0.001/ B = 79.5, p = 0.006), but not with VEP P100 latencies. In the confirmatory MS cohort, lower NFM was associated with thinner retinal nerve fibre layer ( B = 1.351, p < 0.001) and increased mfVEP P100 latencies ( B = −1.159, p < 0.001). Conclusions: Structural neuro-axonal visual pathway damage is an important driver of motion perception impairment in MS and NMOSD.

ObjectivesTo examine whether the dynamic range of 1.25% low-contrast visual acuity (LCVA) measurement in MS patients with optic neuritis (ON) can be improved by using the Early Treatment Diabetic Retinopathy Study (ETDRS) letter scoring method.MethodsLCVA was tested using 2.5% and 1.25% low contrast ETDRS-style 4m Sloan letter charts. When ≥20 letters were read correctly, the letter score was equal to letter count plus 30. If Results51 relapsing-remitting MS patients with unilateral ON were enrolled and 60.8% ON eyes had a 1.25% LCVA letter count worse than 1 line (5 letters). In ON eyes with DiscussionGiven ON with VEP monitoring has been frequently used as a model in MS remyelination clinical trials, our proposed ETDRS-style LCVA letter scoring method may be considered to enhance the functional outcome measure, which is necessary for regulatory approval.

ObjectivesPeople with Multiple Sclerosis (MS) have a larger choroid plexus (CP) volume than healthy controls. We investigated CP volume in early MS by quantitatively assessing brain MRI scans in patients presenting with optic neuritis (ON) as a clinically isolated syndrome (CIS), compared to a cohort with established Relapsing Remitting Multiple Sclerosis (RRMS) and healthy controls.MethodsPre- and post-gadolinium 3D-T1, 3D FLAIR and diffusion-weighted images were acquired from 44 CIS ON patients at baseline, 1, 3, 6 and 12 months after the onset of ON. Fifty RRMS patients and 50 healthy controls were also included for comparison.ResultsANOVA revealed significantly larger CP volumes in both ON CIS and RRMS groups compared to healthy controls (pTwenty-three ON CIS patients who converted to CDMS during 10 years of follow-up demonstrated CP volume similar to RRMS patients, but significantly larger compared to healthy controls (pA significant (∼6%) transient increase of CP volume was observed following a new bout of inflammation, which, however, returned to pre-inflammatory state few months later. CP volume was not associated with the severity of acute inflammation of the optic nerve or long-term optic nerve axonal loss, not with brain lesion load or severity of tissue damage within lesions.InterpretationOur data demonstrate that enlarged CP can be observe very early in a disease, transiently reacts to acute inflammation, but not associated with the degree of tissue destruction.

Background: Change in ventricular volume has been suggested as surrogate measure of central brain atrophy (CBA) applicable to the everyday management of multiple sclerosis (MS) patients. Objectives: We investigated the contribution of inflammatory activity (including the severity of lesional tissue damage) to CBA. Methods: Fifty patients with relapsing–remitting multiple sclerosis (RRMS) were enrolled. Lesional activity during 4 years of follow-up was analysed using custom-build software, which segmented expanding part of the chronic lesions, new confluent lesions and new free-standing lesions. The degree of lesional tissue damage was assessed by change in mean diffusivity (MD). Volumetric change of lateral ventricles was used to measure CBA. Results: During follow-up, ventricles expanded on average by 12.6% ± 13.7% (mean ± SD). There was a significant increase of total lesion volume, 69.3% of which was due to expansion of chronic lesions. Correlation between volume of combined lesional activity and CBA ( r2 = 0.67) increased when lesion volume was adjusted by the degree of tissue damage severity ( r2 = 0.81). Regression analysis explained 90% of CBA variability, revealing that chronic lesion expansion was by far the largest contributor to ventricular enlargement. Discussion: CBA is almost entirely explained by the combination of the volume and severity of lesional activity. The expansion of chronic lesions plays a central role in this process.

Fingolimod (FTY720) is an oral drug approved by the Food and Drug Administration (FDA) for management of multiple sclerosis (MS) symptoms, which has also shown beneficial effects against Alzheimer's (AD) and Parkinson's (PD) diseases pathologies. Although an extensive effort has been made to identify mechanisms underpinning its therapeutic effects, much remains unknown. Here, we investigated Fingolimod induced proteome changes in the cerebellum (CB) and frontal cortex (FC) regions of the brain which are known to be severely affected in MS, using a tandem mass tag (TMT) isobaric labeling-based quantitative mass-spectrometric approach to investigate the mechanism of action of Fingolimod. This study identified 6749 and 6319 proteins in CB and FC, respectively, and returned 2609 and 3086 differentially expressed proteins in mouse CB and FC, respectively, between Fingolimod treated and control groups. Subsequent bioinformatics analyses indicated a metabolic reprogramming in both brain regions of the Fingolimod treated group, where oxidative phosphorylation was upregulated while glycolysis and pentose phosphate pathway were downregulated. In addition, modulation of neuroinflammation in the Fingolimod treated group was indicated by upregulation of retrograde endocannabinoid signaling and autophagy pathways, and downregulation of neuroinflammation related pathways including neutrophil degranulation and the IL-12 mediated signaling pathway. Our findings suggest that Fingolimod may exert its protective effects on the brain by inducing metabolic reprogramming and neuroinflammation pathway modulation.

Background: Slow-burning inflammation is putatively associated with lesion expansion and leads to progressive loss of axons and disability worsening. Objective: To investigate the incidence and extent of chronic white matter lesion expansion in relapsing–remitting multiple sclerosis (RRMS) patients and to evaluate its relationship with biomarkers of disease progression. Methods: Pre- and post-gadolinium T1, fluid-attenuated inversion recovery (FLAIR) and diffusion tensor images were acquired from 33 patients. Lesional activity were analysed between baseline and 48 months using custom-designed software. Results: A total of 569 lesions were identified as chronic at baseline, of which 261 were expanding, 236 were stable and 72 were shrinking. In addition, 139 new lesions (both confluent and free-standing) were observed. Chronic lesion expansion was associated with patient’s age and accounted for the bulk (67.3%) of total brain lesion volume increase, while only 32.7% was attributable to new lesion formation. Change in chronic lesion volume correlated with the rate of brain atrophy ( r = −0.57, p = 0.001), change of Expanded Disability Status Scale (EDSS; r = 0.38, p = 0.03) and an increase of isotropic diffusivity inside the lesions ( r = 0.75, p Conclusion: Expansion of chronic lesions in RRMS patients is the primary determinant of increased T2 total lesion load. It significantly contributes to disease progression and partially driving axonal loss inside the lesions and brain damage outside of lesional tissue.

PURPOSE Acute focal demyelination is the characteristic feature of multiple sclerosis, with the majority of damaged axons undergoing limited remyelination and forming chronic lesions. Potential remyelinating agents are currently under development and there is therefore an urgent need for reliable in vivo biomarkers of remyelination. This study aimed to investigate potential changes in multifocal visual evoked potentials' (mfVEPs) latency in a cohort of relapsing-remitting multiple sclerosis (RRMS) patients. The potential sample size required for a remyelination-based clinical trial using different treatment effect sizes and the mfVEP latency as an outcome measure was also estimated. METHODS A total of 50 RRMS consecutive patients with no previous history of optic neuritis in at least one eye and 15 normal controls of similar age and gender composition were prospectively enrolled. Fifteen patients had a history of unilateral ON more than 12 months earlier, whereas 41 patients demonstrated optic radiations lesions on MRI at baseline. Most patients were on disease modifying therapy. A mfVEP was recorded at baseline and 12 months later. RESULTS At baseline, the mfVEP latency in RRMS patients was delayed compared with normal controls in both optic neuritis and nonoptic neuritis eyes. Latency delay was significantly correlated to optic radiation lesion volume (R2 = 0.38, P < 0.001). There was no significant latency change in multiple sclerosis patients' eyes or optic neuritis and nonoptic neuritis eyes over the follow-up period with latency remaining remarkably constant. This was despite the fact that 46 of 50 patients were on disease-modifying therapies, implying current treatments do not affect myelination in chronic RRMS cases. Sample size calculations to evaluate an additional or alternative remyelinating agent, based on a 40% treatment effect, revealed that a relatively small sample size (78 patients) would be required to demonstrate efficacy in future trials of remyelination therapies. CONCLUSIONS Given its known sensitivity for latency changes and the stability found in this RRMS population, the mfVEP represents an ideal biomarker to assess the degree of latency recovery that may be achieved by remyelination in multiple sclerosis.

Background and Objectives: Expansion of chronic lesions in multiple sclerosis (MS) patients and recently described cerebrospinal fluid (CSF)-related gradient of tissue damage are linked to microglial activation. The aim of this study was to investigate whether lesion expansion is associated with proximity to ventricular CSF spaces. Methods: Pre- and post-gadolinium three-dimensional (3D)-T1, 3D FLAIR and diffusion tensor images were acquired from 36 relapsing-remitting MS (RRMS) patients. Lesional activity was analysed between baseline and 48 months at different distances from the CSF using successive 1 mm thick concentric bands radiating from the ventricles. Results: Voxel-based analysis of the rate of lesion expansion demonstrated a clear periventricular gradient decreasing away from the ventricles. This was particularly apparent when lesions of equal diameter were analysed. Periventricular lesional tissue showed higher degree of tissue destruction at baseline that significantly increased during follow-up in bands close to CSF. This longitudinal change was proportional to degree of lesion expansion. Lesion-wise analysis revealed a gradual, centrifugal decrease in the proportion of expanding lesions from the immediate periventricular zone. Discussion: Our data suggest that chronic white matter lesions in close proximity to the ventricles are more destructive, show a higher degree of expansion at the lesion border and accelerated tissue loss in the lesion core.

Background and ObjectivesThe expansion of long-standing multiple sclerosis (MS) lesions and an enlargement of choroid plexus are linked to chronic inflammation and microglial activation. In the current study, we investigated the association between plexus volume and subsequent lesion expansion in patients with relapsing remitting MS.MethodsPre- and post-gadolinium 3D-T1, 3D FLAIR and diffusion tensor images were acquired from 49 patients with relapsing-remitting MS. Choroid plexus volume and lesion activity were analysed between baseline and 48 months.ResultsPlexus volume remained stable during follow-up period. There was a strong correlation between baseline plexus volume and subsequent rate of chronic lesion expansion (r=0.77, p−5 plexus/TIV ratio predicted future lesion expansion with a sensitivity of 85% and specificity of 76%. Plexus volume larger than a cut-off was associated with >8-fold increased risk of chronic lesion expansion. Furthermore, baseline plexus volume significantly correlated with change of MD in lesional core during the study period (r=0.67, pConclusionOur data demonstrate that baseline plexus volume predicts subsequent expansion of chronic periventricular MS lesions and associated tissue damage.

Sphingosine-1-phosphate receptor (S1PR) signaling regulates diverse pathophysiological processes in the central nervous system. The role of S1PR signaling in neurodegenerative conditions is still largely unidentified. Siponimod is a specific modulator of S1P1 and S1P5 receptors, an immunosuppressant drug for managing secondary progressive multiple sclerosis. We investigated its neuroprotective properties in vivo on the retina and the brain in an optic nerve injury model induced by a chronic increase in intraocular pressure or acute N-methyl-D-aspartate excitotoxicity. Neuronal-specific deletion of sphingosine-1-phosphate receptor (S1PR1) was carried out by expressing AAV-PHP.eB-Cre recombinase under Syn1 promoter in S1PR1

ObjectiveTo update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations.MethodsTo identify studies reporting quantitative OCT results, we performed a PubMed search for the terms “quantitative” and “optical coherence tomography” from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes.ResultsA total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%.ConclusionsThe modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly.

Purpose To compare functional and structural changes in the retina in patients with aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Design Cross-sectional study; biochemical study of human retinas. Participants A total of 181 participants, including 22 consecutive patients (44 eyes) with NMOSD, 131 patients (262 eyes) with multiple sclerosis (MS), and 28 normal subjects (56 eyes). In addition, 8 eyeballs from healthy donors were used for biochemical analysis. Methods Full-field electroretinography (ERG) and spectral-domain OCT were performed in all the subjects. Topography of AQP4 expression and Muller glial distribution were analyzed using Western blotting and immunohistochemistry. Main Outcome Measures Full-field ERG parameters, including amplitudes and peak times. Tissue volume of each of the retinal layers at the fovea by OCT segmentation. Levels of AQP4 expression at different retinal regions. Results The b-wave amplitude was significantly reduced in patients with AQP4-IgG+ NMOSD in scotopic ERGs (compared with AQP4-IgG- subjects, patients with MS, and normal controls) but not in photopic ERGs. Further analysis showed that this b-wave change was mainly caused by reduction of the slow PII component, suggesting specific Muller cell dysfunction. We also found thinning of specific retinal layers at the fovea in patients with AQP4-IgG+ NMOSD, in the Henle fiber outer nuclear layer (HFONL) and the inner segment (IS) layer, but not in the inner nuclear layer (INL), outer plexiform layer (OPL), or outer segment (OS) layer. Furthermore, there was a significant association between foveal HFONL-IS complex thinning and scotopic b-wave amplitude reduction (P = 0.005∼0.01, fixed-effects model). Western blotting demonstrated that Muller cell–specific AQP4 was expressed at a higher level at the fovea than the peripheral retina. Immunohistochemical studies revealed that the specific foveal thinning reflected the topography of AQP4 expression and Muller glial distribution in the human macula. Conclusions This study provides in vivo structural and functional evidence of Muller glial dysfunction in eyes of patients with AQP4-IgG+ NMOSD. Topography of retinal structural change is supported by distribution of Muller cells and patterns of AQP4 expression. The study suggests that visual electrophysiology and retinal imaging could be useful biomarkers to assess the potential retinal astrocytopathy in NMOSD.

To assess differential patterns of axonal loss and demyelination in the optic nerve in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD).Cross-sectional study.One hundred ninety-two participants, including 136 MS patients (272 eyes), 19 NMOSD patients (38 eyes), and 37 healthy control participants (74 eyes).All participants underwent spectral-domain OCT scans and multifocal visual evoked potential (mfVEP) recordings. High-resolution magnetic resonance imaging (MRI) with the diffusion protocol also was performed in all patients.Ganglion cell-inner plexiform layer (GCIPL) thickness and mfVEP amplitude and latency at 5 eccentricities; global and temporal retinal nerve fiber layer thickness.In optic neuritis (ON) eyes, the NMOSD patients had more severe GCIPL loss (P0.001) and mfVEP amplitude reduction (P0.001) compared with MS patients, whereas in contrast, mfVEP latency delay was more evident in MS patients (P0.001). The NMOSD patients showed more morphologic and functional loss at the foveal to parafoveal region, whereas the MS patients showed evenly distributed damage at the macula. Correlation analysis demonstrated a strong structure-function (OCT-mfVEP) association in the NMOSD patients, which was only moderate in the MS patients. In non-ON (NON) eyes, the MS patients showed significantly thinner GCIPL than controls (P0.001), whereas no GCIPL loss was observed in NON eyes in NMOSD. In addition, a significant correlation was found between all OCT and mfVEP measures in MS patients, but not in NMOSD patients. MRI demonstrated significant lesional load in the optic radiation in MS compared to NMOSD eyes (P = 0.002), which was related to the above OCT and mfVEP changes in NON eyes.Our study demonstrated different patterns of ON damage in NMOSD and MS. In MS, the ON damage was less severe, with demyelination as the main pathologic component, whereas in NMOSD, axonal loss was more severe compared with myelin loss. The disproportional mfVEP amplitude and latency changes suggested predominant axonal damage within the anterior visual pathway as the main clinical feature of NMOSD, in contrast to MS, where demyelination spreads along the entire visual pathway.

Highlights • VEPs have largely been replaced by MRI in modern MS diagnosis and management. • Multifocal VEPs are superior to traditional VEPs in evaluating the integrity of the visual system. • Physiological asymmetry limits interpretation of small VEP differences., The assessment of vision is integral to the diagnosis and monitoring of patients with multiple sclerosis (MS). Visual electrophysiology, previously a critical investigation in patients with suspected MS, has in large part been supplanted by magnetic resonance imaging in clinical routine. However, the development of multi-focal visual evoked potentials and the advent of putative re-myelinating therapies that can be monitored with these techniques has led to a resurgence of interest in the field. Here, we review the clinical applications, technical considerations and limitations of visual evoked potentials in the management of patients with MS.

There is a strong interrelationship between eye and brain diseases. It has been shown that neurodegenerative changes can spread bidirectionally in the visual pathway along neuronal projections. For example, damage to retinal ganglion cells in the retina leads to degeneration of the visual cortex (anterograde degeneration) and vice versa (retrograde degeneration). The underlying mechanisms of this process, known as trans-synaptic degeneration (TSD), are unknown, but TSD contributes to the progression of numerous neurodegenerative disorders, leading to clinical and functional deterioration. The hierarchical structure of the visual system comprises of a strong topographic connectivity between the retina and the visual cortex and therefore serves as an ideal model to study the cellular effect, clinical manifestations, and deterioration extent of TSD. With this review we provide comprehensive information about the neural connectivity, synapse function, molecular changes, and pathophysiology of TSD in visual pathways. We then discuss its bidirectional nature and clinical implications in neurodegenerative diseases. A thorough understanding of TSD in the visual pathway can provide insights into progression of neurodegenerative disorders and its potential as a therapeutic target.

ObjectiveTo investigate potential neuroprotective and pro-remyelinating effects of alemtuzumab in multiple sclerosis (MS), using the visual pathway as a model.MethodsWe monitored clinical, multifocal visual evoked potential (mfVEP) and MRI outcomes in 30 patients commencing alemtuzumab for relapsing MS, and a reference group of 20 healthy controls (HCs), over 24 months. Change in mfVEP latency was the primary endpoint; change in optic radiation (OR) lesion diffusion metrics and Mars letter contrast sensitivity over the course of the study were secondary endpoints.ResultsIn patients, we observed a mean shortening of mfVEP latency of 1.21 ms over the course of the study (95% CI 0.21 to 2.21, p=0.013), not altered by correction for age, gender, disease duration or change in OR T2 lesion volume. Mean mfVEP latency in the HC group increased over the course of the study by 0.72 ms (not significant). Analysis of chronic OR T2 lesions (patients) showed an increase in normalised fractional anisotropy and axial diffusivity between baseline and 24 months (both pConclusionWe found evidence of partial lesion remyelination after alemtuzumab therapy, indicating either natural restoration in the context of a ‘permissive’ local milieu; or potentially an independent, pro-reparative mechanism of action. The visual system presents a unique opportunity to study function-structure specific effects of therapy and inform the design of future phase 2 MS remyelination trials.

Purpose Clinical trials for remyelination in multiple sclerosis (MS) require an imaging biomarker. The multifocal visual evoked potential (mfVEP) is an accurate technique for measuring axonal conduction; however, it produces large datasets requiring lengthy analysis by human experts to detect measurable responses versus noisy traces. This study aimed to develop a machine-learning approach for the identification of true responses versus noisy traces and the detection of latency peaks in measurable signals. Methods We obtained 2240 mfVEP traces from 10 MS patients using the VS-1 mfVEP machine, and they were classified by a skilled expert twice with an interval of 1 week. Of these, 2025 (90%) were classified consistently and used for the study. ResNet-50 and VGG16 models were trained and tested to produce three outputs: no signal, up-sloped signal, or down-sloped signal. Each model ran 1000 iterations with a stochastic gradient descent optimizer with a learning rate of 0.0001. Results ResNet-50 and VGG16 had false-positive rates of 1.7% and 0.6%, respectively, when the testing dataset was analyzed (n = 612). The false-negative rates were 8.2% and 6.5%, respectively, against the same dataset. The latency measurements in the validation and testing cohorts in the study were similar. Conclusions Our models efficiently analyze mfVEPs with

Objective There is currently an urgent need for reliable clinical biomarkers of remyelination to be used in Phase 2 and Phase 3 clinical trials. Low contrast visual acuity (LCVA) has been suggested as a functional measure of the integrity of the visual pathway. Therefore, the aim of this study was to elucidate the potential contribution of axonal loss and demyelination to LCVA loss in MS patients. Method In this study, 50 consecutive relapsing remitting MS patients with a previous history of unilateral optic neuritis were enrolled. Using the linear regression model, we assessed the relative contribution of multifocal Visual Evoked Potentials (mfVEP) latency and Retinal Nerve Fiber Layer (RNFL) thickness to LCVA deficit. Results Intereye asymmetry of mfVEP latency and RNFL thickness correlated significantly with intereye asymmetry of LCVA (P

Objective Studies using conventional full‐field visual evoked potentials (ffVEP) have reported subtle abnormalities in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We hypothesize that these abnormalities can be detected in the majority of CIDP patients using enhanced methods. Methods We performed a cross‐sectional noninterventional study comparing 18 CIDP patients and 18 matched healthy controls using multifocal VEP (mfVEP) as a technique with enhanced sensitivity to detect conduction abnormalities across the spectrum of optic nerve fibers. Patients with confounding diseases (ophthalmologic, diabetes mellitus) were excluded. Results The mean amplitude and latency, as well as the low‐contrast visual acuity, did not differ between CIDP patients and controls. Subanalyses revealed latency differences concerning the superior sector of the visual field. Severity markers of CIDP (ODSS, motor nerve conduction velocity) were associated with mfVEP latency delay. Interpretation We could not adduce evidence for clinically or diagnostically relevant visual pathway involvement in CIDP. The latency differences identified were very subtle and restricted to the superior visual field which cannot be readily explained biologically, anatomically, or pathologically. In summary, we conclude that our study revealed no relevant differences in mfVEP parameters between CIDP patients and controls.